Aldose reductase (AR) is an important enzyme involved in the reduction of various aldehyde and carbonyl compounds, including the highly reactive and toxic 4-hydroxynonenal (4-HNE), which has been linked to the progression of various pathologies such as atherosclerosis, hyperglycemia, inflammation, and tumors. AR inhibitors have potential therapeutic benefits for these diseases by reducing lipid peroxidation and mitigating the harmful effects of reactive aldehydes.

In this study, we found that torachrysone-8-O-β-d-glucoside (TG), a natural product isolated from Polygonum multiflorum Thunb., functions as an effective inhibitor of AR, exhibiting potent effects in clearing reactive aldehydes and reducing inflammation. TG up-regulated the mRNA levels of several antioxidant factors downstream of NRF2, especially glutathione S-transferase (GST), which is significantly increased, thus detoxifying 4-HNE by facilitating the conjugation of 4-HNE to glutathione, forming glutathione-4-hydroxynonenal (GS-HNE). By employing a combination of molecular docking, cellular thermal shift assay, and enzyme activity experiments, we demonstrated that TG exhibited strong binding affinity with AR and inhibited its activity and blocked the conversion of GS-HNE to glutathionyl-1,4-dihydroxynonene (GS-DHN), thereby preventing the formation of protein adducts and inducing severe cellular damage.

This study provides novel insights into the anti-inflammatory mechanisms of AR inhibitors and offers potential avenues for developing therapeutic strategies for AR-related pathologies. Our findings suggest that TG, as an AR inhibitor, may hold promise as a therapeutic agent for treating conditions characterized by excessive lipid peroxidation and inflammation. Further investigations are needed to fully explore the clinical potential of TG and evaluate its efficacy in the treatment and management of these complex diseases.

醛糖还原酶(AR) 是一种重要的酶，参与还原各种醛和羰基化合物，包括高反应性和毒性的 4-羟基壬烯醛 (4-HNE)，它与动脉粥样硬化、高血糖等多种病理的进展有关。、炎症和肿瘤。AR抑制剂通过减少脂质过氧化和减轻活性醛的有害影响，对这些疾病具有潜在的治疗益处。

在这项研究中，我们发现从何首乌中分离出的天然产物torachrysone-8- O -β- d -glucoside (TG)可以作为 AR 的有效抑制剂，在清除活性醛和减少炎症方面表现出有效的作用。TG上调NRF2下游多种抗氧化因子的mRNA水平，特别是谷胱甘肽S-转移酶（GST）显着增加，从而通过促进4-HNE与谷胱甘肽缀合形成谷胱甘肽-4-来解毒4-HNE羟基壬烯醛（GS-HNE）。通过分子对接、细胞热位移实验和酶活性实验相结合，我们证明TG与A​​R表现出很强的结合亲和力，抑制其活性，并阻止GS-HNE向谷胱甘肽-1,4-二羟基壬烯（GS）的转化。 -DHN），从而防止蛋白质加合物的形成并诱导严重的细胞损伤。

这项研究为 AR 抑制剂的抗炎机制提供了新的见解，并为开发 AR 相关病理的治疗策略提供了潜在途径。我们的研究结果表明，TG 作为 AR 抑制剂，有望成为治疗以过度脂质过氧化和炎症为特征的疾病的治疗剂。需要进一步的研究来充分探索 TG 的临床潜力并评估其在治疗和管理这些复杂疾病中的功效。